Feeding behavior is an essential action for many living beings including humans. Therefore, if irregularities in feeding behavior occur, disorders, often connected to diseases, will occur in normal life-maintaining activities. Accompanying recent changes of our dietary environment, obesity is now becoming a social problem. In addition, not only is obesity a serious risk factor for life-style diseases such as diabetes, hypertension, and arteriosclerosis; it is also widely known that increased body weight places excessive burdens on joints such as knee joints, causing arthritis and pain. The “diet boom,” etc. show that there is a potentially great percentage of the population hoping to reduce body weight; on the other hand, many cases of feeding problems such as overeating, occurring due to causes such as hereditary neurosis or neurosis due to stress, have been reported.
Therefore, research on and development of agents for preventing or treating obesity, or agents for inhibiting eating, have been vigorously done for a long time. The centrally acting anorectic drug, Mazindol, is now being marketed.
Many appetite control factors such as leptin, have recently been discovered, and the development of anti-obesity agents or anorectic agents which will regulate the functions of these appetite control factors is progressing. In particular, it is known that melanin-concentrating hormone (hereinafter also abbreviated as “MCH”) originates in the hypothalamus and has orexigenic action. In addition, it has been reported that even though the daily behavior of MCH knock-out mice was normal, the amount of feeding by MCH knock-out mice was significantly reduced and their body weights were lighter than those of normal mice [Nature, Vol. 396, p.670, 1998]. This indicates that, if a MCH antagonist was produced, it can be expected to be an excellent anorectic agent or anti-obesity agent; but at present there are no known compound, especially non-peptide type compounds, which possess MCH antagonistic actions.
On the other hand, the following compounds are known as amine derivatives.
1) WO98/38156 describes a compound of the formula: wherein Ar is an optionally substituted ring assembly aromatic group or an optionally substituted condensed aromatic group; X is a bond, etc.; Y is an optionally substituted bivalent C1-6 aliphatic hydrocarbon group which may have an intervening oxygen atom or sulfur atom; R1 and R2 are independently hydrogen atom or an optionally substituted lower alkyl, or R1 and R2, together with the adjacent nitrogen atom, form an optionally substituted nitrogen-containing heterocyclic ring; Ring A is a benzene ring which may have further substituents in addition to the groups of the formula: —X—Ar where each symbol is as defined above; Ring B is a 4- to 8-membered ring which may have further substituents in addition to the group of the formula: —Y—NR1R2 where each symbol is as defined above; with the proviso that, when the condensed ring formed by ring A and ring B is an indole ring, the group of the formula: —X—Ar, where each symbol is as defined above is substituted at the 4-, 6-, or 7-position on the indole ring; or its salt, which has an action of inhibiting the production and secretion of β-amyloid protein.
2) WO95/32967 describes compound of the formula: wherein A is CONR, in which R is hydrogen or C1-6 alkyl; Q is an optionally substituted 5- to 7-membered heterocyclic ring containing 1 to 3 hetero atoms selected from oxygen, nitrogen or sulfur; R1 is hydrogen, halogen, etc.; R2 and R3 are independently hydrogen, halogen, etc.; R4 and R5 are independently hydrogen or C1-6 alkyl; R6 is halogen, hydroxy, etc.; R7 and R8 are independently hydrogen, C1-6 alkyls, etc.; m is 0 to 4; n is 0, 1 or 2; or its salt, which has 5HT1D antagonist activity and can be expected to ameliorate anorexia.
3) WO98/15274 describes a compound of the formula: wherein Ar is phenyl, etc.; X is —O— or —S—; Y is CR5R5′— where R5′ is H and R5 is —H, etc.; Z is —CH2— or —N—; R is H or —(C1-C6) alkyl; R1 and R2 are independently —(C1-C6) alkyl, etc.; R3 is H etc.; R4 is hydrogen, etc.; m is an integer of 0 to 2; q is 0 or 1; n is an integer of 0 to 4; p is an integer of 1 to 6; t is an integer of 1 to 4; which has an anti-oxidant activity and can be expected to ameliorate Alzheimer's disease.
4) EP533266 describes a compound of the formula: wherein R1 is halogen, etc.; R2 is phenyl optionally substituted by 1 or 2 substituents selected from halogen, etc.; R3 is R4 and R5 are independently hydrogen, halogen, etc.; R11 is hydrogen or C1-6 alkyl; which has 5HT1D antagonist activity, and can be expected to ameliorate anorexia.
5) DE2502588 describes a compound of the formula: wherein R1 is hydrogen, or lower alkyl such as Me, Et, etc.; NR2R3 is NH2, a primary amine such as NHMe, etc., a secondary amine such as NEt2, NBu2, etc., or a cyclic amine such as pyrrolidinyl, piperidinyl, morpholinyl, etc.; R4 and R5 are hydrogen, lower alkyl such as Me, etc., lower alkoxy such as OMe, etc., or halogen; R6 is hydrogen, or lower alkyl such as Me, Et, etc.; R7 is H, lower alkyl such as Me, Et, etc., COR8 (R8 is alkoxy, aryloxy, NR9R10 (NR9R10 is NH2, an optionally substituted primary amine such as NHMe, etc., secondary amine such as NEt2, NBu2, etc., or a cyclic amine such as pyrrolidinyl, piperidinyl, morpholinyl, etc.)); A is an alkyl chain such as —CH2—, —CH2CH2—, etc., which can be expected to ameliorate hypertrophy of the small intestine.
6) J. Chem. Soc., 4678 (1962) or J. Heterocycl. Chem., 24, 345 (1987) describes a compound of the formula: wherein R1 is hydrogen, or alkyl such as Me, Et, etc.; R2 is hydrogen, halogen or a carboxylic acid ester, which has folic acid antagonistic activity.
There has been great desire for the development of a melanin-concentrating hormone antagonist which is useful as an agent for preventing or treating obesity, excellent in oral absorbency, and safe.